Thermal irreversible gel corneal contact lens formed in situ

ABSTRACT

Balanced pH, thermo-irreversible gels comprising a polyoxyalkylene compound and an ionic polysaccharide are ideal materials for the formation of a protective contact lens over the cornea of the eye of a mammal.

This application is a continuation application of Ser. No. 08/264,404,filed Jun. 23, 1994, now abandoned, which is a continuation applicationof Ser. No. 07/604,701, filed Oct. 26, 1990, now U.S. Pat. No.5,376,693.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to ophthalmic corneal protective devicescomprising an aqueous gel.

2. Description of the Prior Art

Corneal protective devices are needed in cases in which corneal injuryoccurs and the immobilization of the eye using an eye patch is notresorted to. Molded collagen shields have been developed for this use.These are often not satisfactory because they lack sufficientflexibility to conform to the individual corneal curvature. The clinicaluses of collagen shields are disclosed by Poland et al in Journal ofCataract Refractive Surgery, Volume 14, September 1988, pages 489-491.The author describes the use of collagen shields immersed in tobramycinsolution in order to rehydrate the collagen prior to use. These aredescribed as useful following cataract extraction or in patients havingnonsurgical epithelial healing problems. More rapid healing ofepithelial defects after surgery resulted from the use of the collagenshield. Collagen shields have also been utilized as agents for thedelivery of drugs to the cornea as disclosed in Reidy et al Cornea, inpress, 1989 the Raven Press, Ltd., New York and Shofner et al,Opthalmology Clinics of North America, Vol. 2, No. 1, March 1989, pages15-23.

Over the years, methods have been developed to achieve the efficientdelivery of a therapeutic drug to a mammalian body part requiringpharmaceutical treatment. Use of an aqueous liquid which can be appliedat room temperature as a liquid but which forms a semisolid gel, whenwarmed to body temperature, which readily conforms to corneal curvature,has been utilized as a vehicle for drug delivery since such a systemcombines ease of application, improved patient tolerance, and greaterretention at the site requiring treatment than would be the case if theaqueous composition were not converted to a gel as it is warmed tomammalian body temperature. In U.S. Pat. No. 4,188,373, PLURONIC®polyols are used in aqueous compositions to provide thermally gellingaqueous systems. Adjusting the concentration of the polymer provides thedesired sol-gel transition temperature, that is, the lower theconcentration of polymer, the higher the sol-gel transition temperature,after crossing a critical concentration minimum, below which a gel willnot form. Other polyoxyalkylene gel compositions are disclosed in U.S.Pat. No. 4,810,503 and U.S. Pat. No. 4,879,109.

In U.S. Pat. Nos. 4,474,751; '752; '753; and 4,478,822 drug deliverysystems are described which utilize thermosetting gels; the uniquefeature of these systems is that both the gel transition temperatureand/or the rigidity of the gel can be modified by adjustment of the pHand/or the ionic strength, as well as by the concentration of thepolymer.

Other patents disclosing pharmaceutical compositions which rely upon anaqueous gel composition as a vehicle for the application of the drug areU.S. Pat. Nos. 4,883,660; 4,767,619; 4,511,563; and 4,861,760.Thermosetting gel systems are also disclosed for application to injuredmammalian tissues of the thoracic or peritoneal cavities in U.S. Pat.No. 4,911,926.

Ionic polysaccharides have been used in the application of drugs bycontrolled release. Such ionic polysaccharides as chitosan or sodiumalginate are disclosed as useful in providing spherical agglomerates ofwater-insoluble drugs in the Journal of Pharmaceutical Sciences volume78, number 11, November 1989, Bodmeier et al. Alginates have also beenused as a depot substance in active immunization, as disclosed in theJournal of Pathology and Bacteriology volume 77, (1959), C. R. Amies.Calcium alginate gel formulations have also found use as a matrixmaterial for the controlled release of herbicides, as disclosed in theJournal of Controlled Release, 3 (1986) pages 229 -233, Pfister et al.Alginates have also been used to form hydrogel foam wound dressings, asdisclosed in U.S. Pat. No. 4,948,575.

In U.S. Pat. No. 3,640,741, a molded plastic mass composed of thereaction product of a hydrophilic colloid and a cross-linking agent suchas a liquid polyol, also containing an organic liquid medium such asglycerin, is disclosed as useful in the controlled release of medicationor other additives. The hydrophilic colloid can be carboxymethylcellulose gum or a natural alginate gum which is cross-linked with apolyol. The cross-linking reaction is accelerated in the presence ofaluminum and calcium salts.

In U.S. Pat. No. 4,895,724, compositions are disclosed for thecontrolled release of pharmacological macromolecular compounds containedin a matrix of chitosan. Chitosan can be cross-linked utilizingaldehydes, epichlorohydrin, benzoquinone, etc.

In U.S. Pat. No. 4,795,642, there are disclosed gelatin-encapsulated,controlled-release compositions for release of pharmaceuticalcompositions, wherein the gelatin encloses a solid matrix formed by thecation-assisted gellation of a liquid filling composition incorporatinga vegetable gum together with a pharmaceutically-active compound. Thevegetable gums are disclosed as polysaccharide gums such as alginateswhich can be gelled utilizing a cationic gelling agent such as analkaline earth metal cation.

While the prior art is silent with respect to aqueous corneal protectivecompositions, the alginate hydrogel foam wound dressings disclosed inU.S. Pat. No. 4,948,575, cited above, are of interest in disclosingcompositions which absorb wound exudate without appreciable swelling.These compositions contain a water soluble alginate, an effervescentcompound which effervesces upon reaction with an acid, a water solubleacid, and a water insoluble di- or trivalent metal salt. U.S. Pat No.4,255,415 is also of interest in disclosing a polyvinyl alcohol basedophthalmic gel for drug delivery. Osmotic drug delivery systems aredisclosed in U.S. Pat. No. 4,439,196 which utilize a multi-chambercompartment for holding osmotic agents, adjuvants, enzymes, drugs,pro-drugs, pesticides, and the like. These materials are enclosed bysemipermeable membranes so as to allow the fluids within the chambers todiffuse into the environment into which the osmotic drug delivery systemis in contact. The drug delivery device can be sized for oral ingestion,implantation, rectal, vaginal, or occular insertion for delivery of adrug or other beneficial substance. Since this drug delivery devicerelies on the permeability of the semipermeable membranes to control therate of delivery of the drug, the drugs or other pharmaceuticalpreparations, by definition, are not isotonic with mammalian blood.

SUMMARY OF THE INVENTION

Compositions and a process are disclosed for corneal protective devices.The compositions can be formed in situ and are compositions useful inprotecting the cornea subsequent to injury, surgical or otherwise. Thecompositions in one embodiment of the invention provide aphysiologically acceptable aqueous media which has a buffered pH and isosmotically balanced, preferably, so as to provide an isotonic mixturewhich is iso-osmotic with body fluids and has a pH similar to bodilyfluids, such as lacrimal tears. The pH and osmotic pressure of lacrimaltears is about PH 7.4 and 290 mOsm/kg. In addition, the compositionsare, optionally, sterilized so as to insure that the protectivecompositions of the invention do not provide a source of infection.

Polyphase systems are also useful and may contain non-aqueous solutes,non-aqueous solvents, and other non-aqueous additives. Homogeneous,polyphase systems can contain such additives as water insoluble highmolecular weight fatty acids and alcohols, fixed oils, volatile oils andwaxes, mono-, di-, and triglycerides, and synthetic, water insolublepolymers without altering the functionality of the system.

The compositions of the invention in one embodiment comprise aqueousmixtures of a polyoxyalkylene polymer and an ionic polysaccharide,optionally containing a latent counter-ion to gel the polysaccharideupon release of the counter-ion and to render the gelled mixturethermally irreversible so that it remains a gel upon cooling and thus isrendered durable at ambient temperature. The counter-ion can bemicroencapsulated in a heat sensitive medium, for instance, the walls ofthe microcapsule can be made of mono-, di-, or tri-glycerides or othernatural or synthetic heat sensitive polymer medium. Alternatively, ionexchange resins can be incorporated in the compositions of the inventionso as to release the desired counter-ion upon contact with anenvironment opposite in pH to the pH of the ion exchange resin. Theaqueous mixture can be delivered to the cornea of the mammalian body asa low viscosity liquid at ambient temperatures which, upon contact withthe higher temperature mammalian body, forms a semi-solid gel having avery high viscosity. Release of the counter-ion further strengthens thegel and renders it irreversible upon cooling to ambient temperature.Alternatively, a two part system can be used in which the counter-ioncan be separately applied to the semi-solid gel formed by thepolyoxyalkylene polymer upon contact with the cornea. This furtherstrengthens the gel and renders it irreversible upon cooling. Becausethe preferred compositions of the invention are low viscosity liquids atambient temperatures, they easily coat the cornea insuring maximumcontact between exposed tissue and the composition of the invention. Thegel compositions of the invention can be peeled away subsequent toapplication, if desired. The gels are gradually weakened upon exposureto mammalian body pH conditions but provide a durable protection forinjured corneal tissue against eyelid abrasion.

A wide variety of polyoxyalkylene polymers are suitable for thepreparation of the pharmaceutical compositions of the invention.Generally, it is necessary to adjust the polymer concentration inaqueous solution so as to obtain the desired sol-gel transitiontemperature in order that the compositions can be provided as lowviscosity liquids at ambient temperature, yet form semi-solid gels atmammalian body temperatures. In addition to the concentration of thepolymer other suitable excipients must be added so as to provide thedesired pH and isotonic, iso-osmotic properties.

The useful polymers which provide the sol-gel characteristics of thepharmaceutical compositions of the invention are, preferably,polyoxyalkylene block copolymers.

The ionic polysaccharides are natural polymers such as chitosan oralginates. Aqueous solutions of alginate ionic polysaccharides form gelsupon contact with aqueous solutions of counter-ions such as calcium,strontium, aluminum, etc. Aqueous solutions of chitosan form gels uponcontact with a metal tripolyphosphate counter-ion. The discovery formingthe basis of this application is that when ionic polysaccharides arepresent in aqueous solutions in admixture with certain polyoxyalkyleneblock copolymers and a counter-ion, that such mixtures formthermally-irreversible gels instead of the thermo-reversible gels knownto form with aqueous solutions of certain polyoxyalkylene blockcopolymers.

DESCRIPTION OF THE DRAWING

The drawing provides a curve showing the penetration, as measured by aPrecision Universal Penetrometer, of a 20mm thickness aqueous gelcomprising poloxamer 407 and an alginate prepared in accordance with theprocedure of Example 1. The scale at the left side of the plot indicatesthe depth of penetration, while the scale on the bottom of the plotindicates the temperature of the composition when tested. The arrow inthe plot indicates the point at which an aqueous solution of calciumions at a concentration of 0.137 molar is made to contact the gelledpoloxamer 407/alginate solution so as to render thermally irreversiblethe gelled mixture and prevent it from becoming fluid at ambienttemperature.

DETAILED DESCRIPTION OF THE INVENTION

It has been found that aqueous vehicles containing a polyoxyalkyleneblock copolymer, which have the unique feature of being liquid atambient temperatures and transitioning at mammalian body temperatures toa semi-solid gel, can be rendered thermally irreversible (no longer aliquid at ambient temperature) and resistant to shear thinning. Uponcontacting the mixture with a counter-ion, the polyoxyalkylene polymeraqueous gel becomes more resistant to penetration by the inclusion of apolysaccharide in admixture with the polyoxyalkylene polymer. Thecompositions can be made isotonic or iso-osmotic and adjusted to the pHof mammalian body fluids, such as lacrimal tears. The pH and osmoticpressure of such bodily fluids are 7.4 and 290 mOsm/kg, respectively. Itis advantageous to provide a protective corneal contact lens formed insitu in order to protect injured corneal tissue. It is desirable toprovide such protective corneal contact lens in an aqueous media havinga pH and osmotic pressure which match those of bodily fluids.Optionally, the compositions of the invention can be provided in asterile condition.

The block copolymer compositions of the invention comprise: at least onepolyoxyalkylene block copolymer of the formula

    Y((A).sub.n --E--H).sub.x                                  (I)

wherein A is a polyoxyalkylene moiety having an oxygen/carbon atom ratioof less than 0.5, x is at least 2, Y is derived from water or an organiccompound containing x reactive hydrogen atoms, E is a polyoxyalkylenemoiety constituting at least about 60% by weight of the copolymer, n hasa value such that the average molecular weight of A is at least about500 to about 900, as determined by the hydroxyl number of a hydrophobebase intermediate,

    Y((A).sub.n --H).sub.x                                     (II)

and the total average molecular weight of the copolymer is at leastabout 5,000.

Determination of the average molecular weight via hydroxyl number is anend group analysis which reflects the number of molecules per unitweight of the polymer mixture. The number of molecules is determined bycounting the number of terminal hydroxyl groups in a sample. Any methodknown in the art may be used to count the number of hydroxyl groups,such as reaction with a titratable reagent (Ogg, et al. Ind. Eng. Chem.Anal. Ed. 17:394-397(1945); Conix, Makromol. Chem., 26:226-235 (1958)),or use of infrared spectroscopy (Ward, Trans. Faraday Soc., 53:1406-1414(1957); Daniels, et al., J. Polymer Sci., 33:161-170 (1958)).

Based on the number of terminal hydroxyl groups per molecule (e.g., twoper molecule in the case of poloxamers), the number of molecules iscalculated, preferably expressed as a molar quantity. The averagemolecular weight is then determined by dividing the weight of the sampleby the number of moles of the polymer.

Generally, the polyoxybutylene-based block copolymers useful in thecompositions of the invention are prepared by first condensing 1,2butylene oxide with a water soluble organic compound initiatorcontaining 1 to about 6 carbon atoms, such as, 1,4 butylene glycol orpropylene glycol and at least 2 reactive hydrogen atoms to prepare apolyoxyalkylene polymer hydrophobe of at least about 500, preferably, atleast about 1000, most preferably, at least about 1500 average molecularweight. Subsequently, the hydrophobe is capped with an ethylene oxideresidue. Specific methods for preparing these compounds are described inU.S. Pat. No. 2,828,345 and British Patent No. 722,746, both of whichare hereby incorporated by reference.

Useful polyoxybutylene based block copolymers conform to the followinggeneric formula:

    HO(C.sub.2 H.sub.4 O).sub.b (C.sub.4 H.sub.8 O).sub.a (C.sub.2 H.sub.4 O).sub.b H                                                (III)

wherein a and b are integers such that the hydrophobe base representedby (C₄ H₈ O) has a molecular weight of at least about 500, preferably,at least about 1000 and most preferably, at least about 3000, asdetermined by hydroxyl number, the polyoxyethylene chain constituting atleast about 60%, preferably, at least about 70% by weight of thecopolymer and the copolymer having a total average molecular weight ofat least about 5000, preferably, at least about 10,000, and mostpreferably, at least about 15,000.

The copolymer is characterized in that all the hydrophobic oxybutylenegroups are present in chains bonded to an organic radical at the formersite of a reactive hydrogen atom thereby constituting a polyoxybutylenebase copolymer. The hydrophilic oxyethylene groups are used to cap thepolyoxybutylene base polymer.

Polyoxyethylene-polyoxypropylene block copolymers which can be used toform aqueous gels can be represented by the following formula:

    HO(C.sub.2 H.sub.4 O).sub.b (C.sub.3 H.sub.6 O).sub.a (C.sub.2 H.sub.4 O).sub.b H                                                (IV)

wherein a and b are integers such that the hydrophobe base representedby (C₃ H₆ O)a has a molecular weight of at least about 900, preferably,at least about 2500, most preferably, at least about 4000 averagemolecular weight, as determined by hydroxyl number; the polyoxyethylenechain constituting at least about 60%, preferably, at least about 70% byweight of the copolymer and the copolymer having a total averagemolecular weight of at least about 5000, preferably, at least about10,000, and most preferably, at least about 15,000.

Polyoxyethylene-polyoxypropylene block copolymer adducts of ethylenediamine which can be used may be represented by the following formula:##STR1## wherein a and b are integers such that the copolymer may have(1) a hydrophobe base molecular weight of at least about 2000,preferably, at least about 3000, and most preferably, at least about4500, (2) a hydrophile content of at least about 60%, preferably, atleast about 70% by weight, and (3) a total average molecular weight ofat least about 5000, preferably, at least about 10,000 and mostpreferably, at least about 15,000.

The hydrophobe base of the copolymer of formula V is prepared by addingpropylene oxide for reaction at the site of the four reactive hydrogenatoms on the amine groups of ethylene diamine. An ethylene oxide residueis used to cap the hydrophobe base. The hydrophile polyoxyethylenegroups are controlled so as to constitute at least about 60%,preferably, at least about 70% by weight, and most preferably, at leastabout 80% by weight of the copolymer.

The procedure used to prepare aqueous solutions which form gels of thepolyoxyalkylene block copolymers is well known. Either a hot or coldprocess for forming the solutions can be used. A cold technique involvesthe steps of dissolving the polyoxyalkylene block copolymer at atemperature of about 5° to about 10° C. in water. When solution iscomplete the system is brought to room temperature whereupon it forms agel. If the hot process of forming the gel is used the polymer is addedto water heated to a temperature of about 75° C. to about 85° C. withslow stirring until a clear homogenous solution is obtained. Uponcooling, a clear gel is formed. Block copolymer gels containingpolyoxybutylene hydrophobes must be prepared by the above hot process,since these will not liquify at low temperatures.

As used herein, the term "gel" is defined as a solid or semisolidcolloid containing a certain quantity of water. The colloidal solutionwith water is often called a "hydrosol".

The organic compound initiator which is utilized in the process for thepreparation of the polyoxyalkylene block copolymers generally is wateror an organic compound and can contain a plurality of reactive hydrogenatoms. Preferably, Y in formulas I and II above is defined as derivedfrom a water soluble organic compound having 1 to about 6 carbon atomsand containing x reactive hydrogen atoms where x has a value generally,of at least 1, preferably, a value of at least 2. Falling within thescope of the compounds from which Y is derived from water solubleorganic compounds having at least two reactive hydrogen atoms are watersoluble organic compounds such as propylene glycol, glycerin,pentaerythritol, trimethylolpropane, ethylene diamine, and mixturesthereof and the like.

The oxypropylene chains can optionally contain small amounts of at leastone of oxyethylene or oxybutylene groups. Oxyethylene chains canoptionally contain small amounts of at least one of oxypropylene oroxybutylene groups. Oxybutylene chains can optionally contain smallamounts of at least one of oxyethylene or oxypropylene groups. Thephysical form of the polyoxyalkylene block copolymers can be a viscousliquid, a paste, or a solid granular material depending upon themolecular weight of the polymer. Useful polyoxyalkylene block copolymersgenerally have a total average molecular weight of about 5,000 to about50,000, preferably, about 5,000 to about 35,000 and most preferably,about 10,000 to about 25,000.

In addition to those polyoxyalkylene block copolymers referred to above,which are suitable in the formation of the pharmaceutical compositionsof the invention, other polyoxyalkylene polymers which form gels at lowconcentrations in water are suitable. One such polymer is described inU.S. Pat. No. 4,810,503, incorporated herein by reference. Thesepolymers are prepared by capping conventional polyether polyols with analpha-olefin epoxide having an average of about 20 to about 45 carbonatoms, or mixtures thereof. Aqueous solutions of these polymers gel incombination with surfactants, which can be ionic or nonionic. Thecombination of the capped polyether polymers and the surfactants provideaqueous gels at low concentrations of the capped polymer and surfactant,which generally do not exceed 10% by weight total. Detailed methods ofpreparing these aqueous gels are disclosed in U.S. Pat. No. 4,810,503.Preparation of said aqueous gels is generally described below. Preferredsurfactants for use in preparing these gels are also disclosed in saidpatent.

A conventional copolymer polyether polyol is prepared by preparing blockor heteric intermediate polymers of ethylene oxide and at least onelower alkylene oxide having 3 to 4 carbon atoms as intermediates. Theseare then capped with the alpha-olefin epoxide to prepare the polymers.Ethylene oxide homopolymers capped with said alpha-olefin oxides arealso useful as intermediates.

The heteric copolymer intermediate is prepared by mixing ethylene oxideand at least one lower alkylene oxide having 3 to 4 carbon atoms with alow molecular weight active hydrogen-containing compound initiatorhaving at least two active hydrogens and preferably, 2 to 6 activehydrogen atoms such as a polyhydric alcohol, containing from 2 to 10carbon atoms and from 2 to 6 hydroxyl groups, heating said mixture to atemperature in the range of about 50° C. to 150° C., preferably from 80°C. to 130° C., under an inert gas pressure preferably from about 30 psigto 90 psig.

A block copolymer intermediate is prepared by reacting either theethylene oxide or said alkylene oxide having 3 to 4 carbon atoms withsaid active hydrogen-containing compound followed by reaction with theother alkylene oxide.

The ethylene oxide and the alkylene oxides having from 3 to 4 carbonatoms are used in said intermediates in amounts so that the resultingpolyether product will contain at least 10 percent by weight, preferablyabout 70 percent to about 90 percent by weight, ethylene oxide residue.The ethylene oxide homopolymer intermediate is prepared by reactingethylene oxide with said active hydrogen-containing compound. Thereaction conditions for preparing the block copolymer and ethylene oxidehomopolymer intermediates are similar to those for the heteric copolymerintermediate. The temperature and pressure are maintained in the aboveranges for a period of about one hour to ten hours, preferably one tothree hours.

The alpha-olefin oxides which are utilized to modify the conventionalpolyether intermediate of the prior art are those oxides and thecommercially available mixtures thereof generally containing an averageof about 20 to 45, preferably about 20 to 30, carbon atoms. The amountof alpha-olefin required to obtain the more efficient capped polyethersis generally about 0.3 to 10 percent, preferably about 4 to 8 percent,of the total weight of the polyethers.

Since the preparation of heteric and block copolymers of alkylene oxidesand ethylene oxide homopolymers are well known in the art, furtherdescription of the preparation of said polymers is unnecessary. Furtherdetails of the preparation of heteric copolymers of lower alkylene oxidecan be obtained in U.S. Pat. No. 3,829,506, incorporated herein byreference. Further information on the preparation of block copolymers oflower alkylene oxides can be obtained in U.S. Pat Nos. 3,535,307;3,036,118; 2,979,578; 2,677,700; and 2,675,619 incorporated herein byreference.

The surfactants may be ionic or non-ionic and many surfactants and typesof surfactants may be employed. While all surfactants may not beeffective in the preparation of the isotonic gels of the instantinvention, the fact that many are effective makes it a simple matter forone skilled in the art to select such surfactant with a minimum of trialand error.

The amounts of capped polyether polymer and surfactant may be as littleas 1.0 percent by weight or less of each depending on the type andamount of the other component. There appears to be no maximum amount ofeither component than that dictated by economic considerations. However,the total amount of capped polymer and surfactant would generally notexceed 10 percent by weight.

The ionic polysaccharides found useful in the present invention arehydrophilic colloidal materials and include the natural gums such asalginate gums, i.e., the ammonium and alkali metal salts of alginic acidand mixtures thereof as well as chitosan, which is a common name for thedeacetylated form of chitin. Chitin is a natural product comprisingpoly-(N-acetyl-D-glucosamine). The alginates are available as drypowders from Protan, Inc., Commack, N.Y. and from Kelco Company, SanDiego, Calif.

Generally, the alginates can be any of the water-soluble alginatesincluding the alkali metal alginates, such as sodium, potassium,lithium, rubidium and cesium salts of alginic acid, as well as theammonium salt, as well as the soluble alginates of an organic base suchas mono-, di-, or tri-ethanolamine, aniline and the like. Generally,about 0.2% to about 2.5% by weight and, preferably, about 0.5% to about1.5% by weight of alginate or chitosan ionic polysaccharides, based uponthe total weight of the composition, are used to obtain thethermo-irreversible compositions of the invention. In general, the drugdelivery composition of the invention will contain about 0.01% to about60% by weight of medicament or pharmaceutical, about 10% to about 50% byweight of the polyoxyalkylene polymer, and about 80% to about 20% byweight of water together with the above amounts of ionic polysaccharide.In special situations, these amounts may be varied to increase ordecrease the dosage or gel properties.

Useful counter-ions for thermo-irreversibly gelling the alginate ionicpolysaccharide in combination with the polyoxyalkylene polymercompositions of the invention are cationic gelling agents, preferably,comprising a divalent or trivalent cation. Useful divalent cationsinclude the alkaline earth metals, preferably, selected from the groupconsisting of calcium and strontium. Useful trivalent cations includealuminum. The most preferred counter-ions for gelling an alginate arecontained in ionic compounds selected from pharmaceutically-acceptablegluconates, flourides, citrates, phosphates, tartrates, sulfates,acetates, borates, chlorides, and the like having alkaline earth metalcations such as calcium and strontium. Especially perferred counter-ioncontaining inorganic salts for use as ionic polysaccharide gellingagents include such inorganic salts as the chloride salts, such asstrontium chloride, calcium chloride, and mixtures thereof. Generally, amolar ratio of counter-ion to chitosan or alginate of about 1:1 to about10:1, preferably, about 2:1 to about 5:1, and, most preferably, about3:1 to about 5:1 is used to render the compositions of the inventionthermally-irreversibly gelled.

While the counter-ion, such as calcium or other counter-ions may beobtained by contact with bodily fluids, it is preferred that thecounter-ion in latent form be added to the alginate ionic polysaccharideand polyoxyalkylene polymer compositions of the invention.Alternatively, a counter-ion can be added to the alginate ionicpolysaccharide and polyoxyalkaline polymer compositions of the inventionutilizing a two part system in which the counter-ion is topicallyapplied to an aqueous solution of the thermally reversible gelpolyoxyalkylene compositions of the invention subsequent to the topicalapplication of such compositions to the cornea. Incorporation of thecounter-ion in a latent form together with the alginate ionicpolysaccharide and polyoxyalkylene polymer compositions of the inventionmay be accomplished by either encapsulating an aqueous solution of oneof the counter-ion gelling agents, previously described above or by theincorporation of the counter-ion gelling agent into a matrix whichprovides for the controlled, slow-release of the gelling agent. Forinstance, the gelatin-encapsulated controlled-release compositionsdisclosed in U.S. Pat. No. 4,795,642, incorporated herein by reference,disclose the preparation of a gelatin shell encapsulating acontrolled-release formulation in which the gelatin composition includescalcium chloride as the gelling agent. Alternatively, the counter-ioncan be incorporated as an aqueous solution of a cationic gelling agentencapsulated in a vesicle composed, for instance, of alpha-tocopherol,as disclosed in U.S. Pat. No. 4,861,580, incorporated herein byreference.

Generally, aqueous solutions of chitosan can be gelled with multivalent,anion gelling agents, preferably, comprising a metal polyphosphate, suchas an alkali metal or ammonium polyphosphates, pyrophosphates, ormetaphosphates. Representative metaphosphate, pyrophosphate, andpolyphosphate gelling agents include sodium and potassium,polyphosphates, sodium and potassium pyrophosphates, sodium andpotassium metaphosphates, and sodium and ammonium (mono-, di-, tri-)phosphates.

Drug delivery systems which are liquid at room temperature and assume asemi-solid form at human body temperature have been proposed, such asthose described in U.S. Pat. No. 4,188,373, which disclose the use ofPLURONIC® polyols. In U.S. Pat. No. 4,861,760 and U.S. Pat. No.4,474,751, ophthalmic drug delivery systems are disclosed which arecharacterized by liquid-gel phase transitions. In the '751 patent,polymers are disclosed which are tetra substituted derivatives ofethylenediamine, propylenediamine, butylenediamine, pentylenediamine, orhexylenediamine. These are described as block copolymers ofpoly(oxypropylene) and poly(oxyethylene) of various chain lengths. Thesepolymers are utilized as aqueous drug delivery vehicles which containfrom 10% to 50% by weight of polymer based on the weight of the totaldrug delivery vehicle. In the '760 patent, the liquid-gel phasetransition compositions for ophthalmological use contain polymers whichform gels at concentrations 10-100 fold lower than those used in systemssuch as the '751 patent, involving thermogellation. Accordingly, thedrug delivery systems of the '760 patent are said to be very welltolerated by the eye. The polymers utilized in the drug deliveryvehicles of the '760 patent are described as polysaccharides obtained byfermentation of a microorganism.

The corneal protective compositions of the invention are an improvementover these prior art ophthalmological drug delivery systems in that thecompositions can be not only optimized for physiological tolerance inthe eye by formulating the compositions so as to have isotoniccharacteristics, but are made more durable because of increasedresistance to shear thinning, as the result of higher gel strength.These latter advantages are obtained by the incorporation of an ionicpolysaccharide in admixture with a polyalkylene polymer. By matching theosmolality of the drug delivery compositions of the invention to thoseof the lacrimal fluid of the eye, it is possible to eliminate burning orother discomfort upon application of the drug delivery systems of theinvention to the eye. The higher gel strength compostions upon contactwith a counter ion for the ionic polysaccharide allow retention of thegel as a protective in situ formed contact lens for long intervals.

If desired, the protective contact lens of the invention may alsocontain preservatives, cosolvents, suspending agents, viscosityenhancing agents, ionic-strength and osmolality adjustors and otherexcipients in addition to the polyoxyalkylene polymer and ionicpolysaccharide. Suitable water soluble preservatives which may beemployed are sodium bisulfite, sodium thiosulfate, ascorbate,benzalkonium chloride, chlorabutanol, thimerosal, phenylmercuric borate,parabens, benzylalcohol phenylethanol and others. These agents may bepresent, generally, in amounts of about 0.001% to about 5% by weightand, preferably, in the amount of about 0.01 to about 2% by weight.

Suitable water soluble buffering agents are alkali or alkaline earthmetal carbonates, phosphates, bicarbonates, citrates, borates, acetates,succinates and the like, such as sodium phosphate, citrate, borate,acetate, bicarbonate, carbonate and tromethamine (TRIS). These agentsare present in amounts sufficient to maintain the pH of the system at7.4±0.2 and preferably, 7.4. As such the buffering agent can be as muchas 5% on a weight basis of the total composition.

Representative buffering agents or salts useful in maintaining the pH atabout 7.4±0.2 are alkali or alkali earth carbonates, chlorides,sulfates, phosphates, bicarbonates, citrates, borates, acetates andsuccinates. Representative preservatives are sodium bisulfite, sodiumthiosulfate, ascorbate, benzalkonium chloride, chlorobutanol,thimerosal, phenylmercuric borate, parabens, benzylalcohol andphenylethanol.

The preparation of the corneal contact lens compositions of theinvention are described below. The Examples which follow are preparedaccording with the following preparation procedure. Since thepolyoxyalkylenes dissolve more completely at reduced temperatures, thepreferred methods of solubilization are to add the required amount ofpolymer to the amount of water to be used. Generally after wetting thepolymer by shaking, the mixture is capped and placed in a cold chamberor in a thermostatic container at about 0° C. to 10° C. in order todissolve the polymer. The mixture can be stirred or shaken to bringabout a more rapid solution of the polymer. The various additives suchas buffers, salts, and preservatives can subsequently be added anddissolved. The desired pH of 7.4±0.2 is obtained by the addition ofappropriate buffering agents.

The following Examples illustrate the various aspects of the inventionbut are not intended to limit its scope. Where not otherwise specifiedthroughout this specification and claims, temperatures are given indegrees centigrade and parts, percentages, and proportions are byweight.

EXAMPLE 1

This Example describes a composition of the invention for ophthalmic useas a protective corneal contact lens. The composition prepared wascharacterized as iso-osmotic, sterile, and having a pH of 7.4±0.2. Anaqueous solution was made of a polyoxyethylene-polyoxypropylene blockcopolymer having the structure generically shown above as Formula IV andhaving a polyoxypropylene hydrophobe base average molecular weight ofabout 4000, a total average molecular weight of about 11,500, andcontaining oxyethylene groups in the amount of about 70% by weight ofthe total weight of copolymer. This copolymer (Formula VI below) is soldunder the trademark PLURONIC® F-127 (also known as Poloxamer 407) by theBASF Corporation, Parsippany, N.J. A solution in TRIS hydrochloridebuffer was made by dissolving said polymer and sodium alginate in cold(4° C.) buffer to give a concentration of 19% by weight polyoxyalkyleneand 1% by weight sodium alginate. More specific solution procedures aredescribed in "Artificial Skin I Preparation and Properties of PLURONICF-127 Gels For Treatment of Burns", Journal of Biomedical MaterialResearch 6, 527, 1972, incorporated herein by reference. The blockcopolymer has the formula: ##STR2## This formulation forms the basis forthe Figure in which the curve shows the penetration of a 20 mm thicknessaqueous gel at various temperatures. After contact of the gel withcalcium ions, as indicated by the vertical line at 40° C., the gelstrength is not reduced or the composition rendered fluid by loweringthe temperature to 25° C.

EXAMPLES 2 and 3

These examples describe pH balanced, thermo-sensitive aqueous systemswhich are suitable for forming a thermally reversible corneal contactlens in situ. Both examples will result in the formation of thermallyirreversible systems upon exposure to an aqueous solution of 2% to 10%by weight calcium chloride. The formulations are:

    ______________________________________                                                        Example 2                                                                            Example 3                                              Ingredient        Percent by weight                                           ______________________________________                                        Poloxamer 407     16.0     16.0                                               (block, BHT free)                                                             Sodium alginate    1.0      1.0                                               Boric acid-Borate Buffer                                                                        82.7     --                                                 pH 7.4                                                                        Phosphate-Borate Buffer                                                                         --       82.7                                               pH 7.4                                                                        Glycerin           0.3      0.3                                               ______________________________________                                    

The formulations are prepared by the "Hot Method", "BWC surfactants ingel cosmetics", I. R. Schmolka, Cosmetics and Toiletries, vol 92, July1977, pages 77-79. The procedure is as follows:

1. The poloxamer blocks (BASF Corp) are melted at 65° C. in a waterjacketed mixing bowl. The mixer used is a Stephan UMC5 mixer-blender(Stephan Machinery, Columbus, Ohio).

2. A weighed amount of buffer is placed in a one liter beaker. Weighedamounts of Glycerin (JT Baker) and Sodium Alginate (Protonal SF120,Protan, Inc.) are added to dissolve and mix.

3. This solution is added to the molten poloxamer and mixed at 65° C.for 15 minutes in a nitrogen atmosphere.

4. The temperature is gradually dropped to 25° C. and then to 15° C. bythe circulation of ice-cold water.

5. The final product is stored overnight at 4° C. in a glass beaker.

6. The next day the following tests were done and the results were asfollows:

    ______________________________________                                        Test              Example 2 Example 3                                         ______________________________________                                        1.    pH              7.37      7.44                                          2.    Osmolality in yelled state                                                                    290       350                                                 (calculated mOsm/kg)                                                                          iso-osmotic                                                                             hyper-osmotic                                 3.    Solution-Gel Profile                                                                          strong gel                                                                              weak gel                                            (Brookfield Viscometer)                                                                       50,000 cps                                                                              1000 cps                                            (10 rpm, at 33° C.)                                              ______________________________________                                    

EXAMPLES 4 and 5

Examples 2 and 3 are repeated substituting for poloxamer 407, 2% byweight of polymer #2, as described in U.S. Pat. No. 4,810,503 and 4% byweight of surfactant #1, as described therein. The balance of thepercentage of Poloxamer 407 used in Examples 2 and 3 is made up with aborate buffer or a phosphate borate buffer, respectively. Theseformulations form soft gels at room temperature which are usefullystiffened upon exposure to a 2% by weight aqueous solution of calciumchloride. Substantially similar pH and osmolality results are obtained.

EXAMPLE 6

Ion exchange resin beads sold under the tradename Duolite were treatedso as to incorporate calcium by first treating a 30 gram sample of theion exchange resin with a solution of 0.1 molar hydrochloric acid so asto allow for the exchange of protons for sodium. After three washingswith 0.1 molar hydrochloric acid, the beads were washed with water andthen washed twice with a 2% aqueous solution of calcium chloride. Eachof the washing steps took place over a period of 16 hours (overnight).The beads were thereafter filtered and washed with water utilizingcoarse filter paper and a Buchner glass filter assembly. The beads werethen left overnight in a desiccator to dry. The dried beads of ionexchange resin which were obtained are utilized in the amount of 2 gramsto fill a first compartment (close to the needle of the syringe) of aglass syringe utilized to apply liquids and dry materials. The syringeis sold under the tradename Hypak. Into the second compartment of thesyringe, there is placed the solution of Example 2. Pushing the plungerof the syringe forward results in mixing the solution of Example 2 withthe ion exchange beads. After 5 to 10 minutes subsequent to mixing, themixture is expelled from the syringe. After an additional 15 minutes theexpelled material forms a thermo-irreversible film on the substrate onwhich it is expelled.

While this invention has been described with reference to certainspecific embodiments, it will be recognized by those skilled in the artthat many variations are possible without departing from the scope andspirit of the invention, and it will be understood that it is intendedto cover all changes and modifications of the invention, disclosedherein for the purposes of illustration, which do not constitutedepartures from the spirit and scope of the invention.

The embodiments of the invention in which an exclusive property orprivilege is claimed are defined as follows:
 1. A protective layerformed in situ on a cornea of the eye of a mammal comprising:(a) anionic polysaccharide; (b) a polyoxyalkylene polyether block copolymerhaving an average molecular weight of about 10,000 to about 100,000 asdetermined by hydroxyl number which is selected from the groupconsisting of1) polyoxyalkylene polyethers prepared by reacting ethyleneoxide and at least one lower alkylene oxide having 3 to 4 carbon atomswith at least one active hydrogen-containing compound having from 3 to10 carbon atoms and from 3 to 6 active hydrogens to prepare a heteric orblock copolymer intermediate and further reacting said copolymerintermediate and further reacting said copolymer intermediate with atleast one alpha-olefin oxide having an average carbon chain length ofabout 20 to about 45 aliphatic carbon atoms and wherein saidalpha-olefin oxide is present in the amount of about 0.3 to 10 percentby weight based upon the total weight of said polyether and 2)polyoxyalkylene polyethers prepared by reacting ethylene oxide with atleast one active hydrogen-containing compound having from 2 to 10 carbonatoms and from 2 to 6 active hydrogens to prepare a homopolymerintermediate and further reacting said homopolymer with at least onealpha-olefin oxide having an average carbon chain length of about 20 to45 aliphatic carbon atoms and wherein said alpha-olefin oxide is presentin the amount of about 0.3 to 10 percent by weight based on the totalweight of said polyether; and (c) an added counter ion whichthermo-irreversibly cross-links the ionic polysaccharide.
 2. Theprotective layer recited in claim 1, wherein said protective layerfurther includes a surfactant.
 3. A protective layer formed in situ on acornea of the eye of a mammal comprising:(a) an ionic polysaccharide;(b) a polyoxyalkylene polyether block copolymer having an averagemolecular weight of about 10,000 to about 100,000 as determined byhydroxyl number which is selected from the group consisting of1)polyoxyalkylene polyethers prepared by reacting ethylene oxide and atleast one lower alkylene oxide having 3 to 4 carbon atoms with at leastone active hydrogen-containing compound having from 3 to 10 carbon atomsand from 3 to 6 active hydrogens to prepare a heteric or block copolymerintermediate and further reacting said copolymer intermediate andfurther reacting said copolymer intermediate with at least onealpha-olefin oxide having an average carbon chain length of about 20 toabout 45 aliphatic carbon atoms and wherein said alpha-olefin oxide ispresent in the amount of about 0.3 to 10 percent by weight based uponthe total weight of said polyether and 2) polyoxyalkylene polyethersprepared by reacting ethylene oxide with at least one activehydrogen-containing compound having from 2 to 10 carbon atoms and from 2to 6 active hydrogens to prepare a homopolymer intermediate and furtherreacting said homopolymer with at least one alpha-olefin oxide having anaverage carbon chain length of about 20 to 45 aliphatic carbon atoms andwherein said alpha-olefin oxide is present in the amount of about 0.3 to10 percent by weight based on the total weight of said polyether; and(c) a counter ion from body fluid which thermo-irreversibly cross-linksthe ionic polysaccharide.
 4. The protective layer recited in claim 3,wherein said protective layer further includes a surfactant.
 5. Theprotective layer recited in claim 1 wherein said protective layerfurther includes a pharmaceutical compound.
 6. The protective layerrecited in claim 4 wherein said protective layer further includes apharmaceutical compound.